tbuckley/cabot-search huggingface dataset:
The Role of Genetics in Clinically Suspect Arthralgia and Rheumatoid Arthritis Development: A Large Cross‐Sectional Study
Authors: Marc P. Maurits, Fenne Wouters, Ellis Niemantsverdriet, Thomas W. J. Huizinga, Erik B. van den Akker, Saskia Le Cessie, Annette H. M. van der Helm‐van Mil, Rachel Knevel
Journal: Arthritis & Rheumatology (2022)

To investigate whether established genetic predictors for rheumatoid arthritis (RA) differentiate healthy controls, patients with clinically suspect arthralgia (CSA), and RA patients.Using analyses of variance, chi-square tests, and mean risk difference analyses, we investigated the association of an RA polygenic risk score (PRS) and HLA shared epitope (HLA-SE) with all participant groups, both unstratified and stratified for anti-citrullinated protein antibody (ACPA) status. We used 3 separate data sets sampled from the same Dutch population (1,015 healthy controls, 479 CSA patients, and 1,146 early classified RA patients). CSA patients were assessed for conversion to inflammatory arthritis over a period of 2 years, after which they were classified as either CSA converters (n = 84) or CSA nonconverters (n = 395).The PRS was increased in RA patients (mean ± SD PRS 1.31 ± 0.96) compared to the complete CSA group (1.07 ± 0.94) and compared to CSA converters (1.12 ± 0.94). In ACPA- strata, PRS distributions differed strongly when comparing the complete CSA group (mean ± SD PRS 1.05 ± 0.94) and CSA converters (0.97 ± 0.87) to RA patients (1.20 ± 0.94), while in the ACPA+ strata, the complete CSA group (1.25 ± 0.99) differed clearly from healthy controls (1.05 ± 0.94) and RA patients (1.41 ± 0.96). HLA-SE was more prevalent in the RA group (prevalence 0.64) than the complete CSA group (0.45), with small differences between RA patients and CSA converters (0.64 versus 0.60) and larger differences between CSA converters and CSA nonconverters (0.60 versus 0.42). HLA-SE prevalence differed more strongly within the ACPA+ strata as follows: healthy controls (prevalence 0.43), CSA nonconverters (0.48), complete CSA group (0.59), CSA converters (0.66), and RA patients (0.79).We observed that genetic predisposition increased across pre-RA participant groups. The RA PRS differed in early classified RA and inflammatory pre-disease stages, regardless of ACPA stratification. HLA-SE prevalence differed between arthritis patients, particularly ACPA+ patients, and healthy controls. Genetics seem to fulfill different etiologic roles.
Towards a better understanding of non-exudative choroidal and macular neovascularization
Authors: Riccardo Sacconi, Serena Fragiotta, David Sarraf, SriniVas R. Sadda, K. Bailey Freund, Mariacristina Parravano, Giulia Corradetti, Diogo Cabral, Vittorio Capuano, Alexandra Miere, Eliana Costanzo, Francesco Bandello, Eric Souied, Giuseppe Querques
Journal: Progress in Retinal and Eye Research (2022)
Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
Authors: Shuting Cao, Yu-Wen Hung, Yi-Chang Wang, Yiyin Chung, Yue Qi, Ching Ouyang, Xiancai Zhong, Weidong Hu, Alaysia Coblentz, Ellie Maghami, Zuoming Sun, H. Helen Lin, David K. Ann
Journal: Theranostics (2022)

Rationale: Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors.Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival.However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood.Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity.Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity.Methods: A syngeneic orthotopic tumor model in Atg5 +/+ and Atg5 flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs).Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4 + , and CD8 + cells tumor infiltration at 14 days and 28 days after MST inoculation.In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion. Results:We showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells.An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8 + T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5 flox/flox mice.Mechanistically, ATG5 deficiency increased glutamine level in tumors.We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5 +/+ mice.Conclusions: Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8 + T cells and Tregs.
Reduced splenic uptake on <sup>68</sup>Ga-Pentixafor-PET/CT imaging in multiple myeloma - a potential imaging biomarker for disease prognosis
Authors: Sabrina Kraus, Philipp Klassen, Malte Kircher, Alexander Dierks, Stefan Habringer, Alexander Gäble, Klaus Martin Kortüm, Niels Weinhold, Valëza Ademaj-Kospiri, Rudolf A Werner, Andreas Schirbel, Andreas K Buck, Peter Herhaus, Hans-Jürgen Wester, Andreas Rosenwald, Wolfgang A Weber, Hermann Einsele, Ulrich Keller, Leo Rasche, Constantin Lapa
Journal: Theranostics (2022)

Beyond being a key factor for tumor growth and metastasis in human cancer, C-X-C motif chemokine receptor 4 (CXCR4) is also highly expressed by a number of immune cells, allowing for non-invasive read-out of inflammatory activity. With two recent studies reporting on prognostic implications of the spleen signal in diffusion-weighted magnetic resonance imaging in patients with plasma cell dyscrasias, the aim of this study was to correlate splenic 68Ga-Pentixafor uptake in multiple myeloma (MM) with clinical parameters and to evaluate its prognostic impact. Methods: Eighty-seven MM patients underwent molecular imaging with 68Ga-Pentixafor-PET/CT. Splenic CXCR4 expression was semi-quantitatively assessed by peak standardized uptake values (SUVpeak) and corresponding spleen-to-bloodpool ratios (TBR) and correlated with clinical and prognostic features as well as survival parameters. Results:68Ga-Pentixafor-PET/CT was visually positive in all MM patients with markedly heterogeneous tracer uptake in the spleen. CXCR4 expression determined by 68Ga-Pentixafor-PET/CT corresponded with advanced disease and was inversely associated with the number of previous treatment lines as compared to controls or untreated smouldering multiple myeloma patients (SUVpeakSpleen 4.06 ± 1.43 vs. 6.02 ± 1.16 vs. 7.33 ± 1.40; P < 0.001). Moreover, reduced splenic 68Ga-Pentixafor uptake was linked to unfavorable clinical outcome. Patients with a low SUVpeakSpleen (<3.35) experienced a significantly shorter overall survival of 5 months as compared to 62 months in patients with a high SUVpeakSpleen >5.79 (P < 0.001). Multivariate Cox analysis confirmed SUVpeakSpleen as an independent predictor of survival (HR 0.75; P = 0.009). Conclusion: These data suggest that splenic 68Ga-Pentixafor uptake might provide prognostic information in pre-treated MM patients similar to what was reported for diffusion-weighted magnetic resonance imaging. Further research to elucidate the underlying biologic implications is warranted.
3p-C-NETA: A versatile and effective chelator for development of Al<sup>18</sup>F-labeled and therapeutic radiopharmaceuticals
Authors: Stephen Ahenkorah, Erika Murce, Christopher Cawthorne, Jessica Pougoue Ketchemen, Christophe M. Deroose, Thomas Cardinaels, Yann Seimbille, Humphrey Fonge, Willy Gsell, Guy Bormans, Maarten Ooms, Frederik Cleeren
Journal: Theranostics (2022)

Background: Radiolabeled somatostatin analogues (e.g.[ 68 Ga]Ga-DOTATATE and [ 177 Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success.[ 18 F]AlF-NOTA-octreotide, a promising 18 F-labeled somatostatin analogue and potential alternative for 68 Ga-DOTA-peptides, is under clinical evaluation.However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar (e.g.Al 18 F-method in combination with therapeutic radiometals 213 Bi/ 177 Lu) or identical (e.g.complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients.In this study we evaluated 3p-C-NETA, as potential theranostic Al 18 F-chelator and present first results of radiosynthesis and preclinical evaluation of [ 18 F]AlF-3p-C-NETA-TATE.Methods: 3p-C-NETA was synthesized and radiolabeled with diagnostic ( 68 Ga, Al 18 F) or therapeutic ( 177 Lu, 161 Tb, 213 Bi, 225 Ac and 67 Cu) radionuclides at different temperatures (25-95 °C).The in vitro stability of the corresponding radiocomplexes was determined in phosphate-buffered saline (PBS) and human serum.3p-C-NETA-TATE was synthesized using standard solid/liquid-phase peptide synthesis.[ 18 F]AlF-3p-C-NETA-TATE was synthesized in an automated AllinOne® synthesis module and the in vitro stability of [ 18 F]AlF-3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum.[ 18 F]AlF-3p-C-NETA-TATE pharmacokinetics were evaluated using µPET/MRI in healthy rats, with [ 18 F]AlF-NOTA-Octreotide as benchmark.Results: 3p-C-NETA quantitatively sequestered 177 Lu, 213 Bi and 67 Cu at 25 °C while heating was required to bind Al 18 F, 68 Ga, 161 Tb and 225 Ac efficiently.The [ 18 F]AlF-, [ 177 Lu]Lu-and [ 161 Tb]Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over the study period.In contrast, [ 67 Cu]Cuand [ 225 Ac]Ac-, [ 68 Ga]Ga-3p-C-NETA were stable in PBS, but not in human serum.[ 18 F]AlF-3p-C-NETA-TATE was obtained in good radiochemical yield and radiochemical purity.[ 18 F]AlF-3p-C-NETA-TATE displayed good in vitro stability for 4 h in all tested conditions.Finally, [ 18 F]AlF-3p-C-NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [ 18 F]AlF-NOTA-Octreotide.Conclusions: 3p-C-NETA is a versatile chelator that can be used for both diagnostic applications (Al 18 F) and targeted radionuclide therapy ( 213 Bi, 177 Lu, 161 Tb).It has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine.
Engineered extracellular vesicles with high collagen-binding affinity present superior <i>in situ</i> retention and therapeutic efficacy in tissue repair
Authors: Dake Hao, Lu Lu, Hengyue Song, Yixin Duan, Jianing Chen, Randy Carney, Jian Jian Li, Ping Zhou, Jan Nolta, Kit S. Lam, J. Kent Leach, Diana L Farmer, Alyssa Panitch, Aijun Wang
Journal: Theranostics (2022)

Although stem cell-derived extracellular vesicles (EVs) have remarkable therapeutic potential for various diseases, the therapeutic efficacy of EVs is limited due to their degradation and rapid diffusion after administration, hindering their translational applications.Here, we developed a new generation of collagen-binding EVs, by chemically conjugating a collagen-binding peptide SILY to EVs (SILY-EVs), which were designed to bind to collagen in the extracellular matrix (ECM) and form an EV-ECM complex to improve EVs' in situ retention and therapeutic efficacy after transplantation.Methods: SILY was conjugated to the surface of mesenchymal stem/stromal cell (MSC)-derived EVs by using click chemistry to construct SILY-EVs.Nanoparticle tracking analysis (NTA), ExoView analysis, cryogenic electron microscopy (cryo-EM) and western-blot analysis were used to characterize the SILY-EVs.Fluorescence imaging (FLI), MTS assay, ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the collagen binding and biological functions of SILY-EVs in vitro.In a mouse hind limb ischemia model, the in vivo imaging system (IVIS), laser doppler perfusion imaging (LDPI), micro-CT, FLI and RT-qPCR were used to determine the SILY-EV retention, inflammatory response, blood perfusion, gene expression, and tissue regeneration.Results: In vitro, the SILY conjugation significantly enhanced EV adhesion to the collagen surface and did not alter the EVs' biological functions.In the mouse hind limb ischemia model, SILY-EVs presented longer in situ retention, suppressed inflammatory responses, and significantly augmented muscle regeneration and vascularization, compared to the unmodified EVs. Conclusion:With the broad distribution of collagen in various tissues and organs, SILY-EVs hold promise to improve the therapeutic efficacy of EV-mediated treatment in a wide range of diseases and disorders.Moreover, SILY-EVs possess the potential to functionalize collagen-based biomaterials and deliver therapeutic agents for regenerative medicine applications.
Machine learning-based identification of tumor-infiltrating immune cell-associated lncRNAs for improving outcomes and immunotherapy responses in patients with low-grade glioma
Authors: Nan Zhang, Hao Zhang, Wantao Wu, Ran Zhou, Shuyu Li, Zeyu Wang, Ziyu Dai, Liyang Zhang, Fangkun Liu, Zaoqu Liu, Jian Zhang, Peng Luo, Zhixiong Liu, Quan Cheng
Journal: Theranostics (2022)

Rationale: Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) involved in the regulation of the immune system and displayed a cell-type-specific pattern in immune cell subsets. Given the vital role of tumor-infiltrating lymphocytes in effective immunotherapy, we explored the tumor-infiltrating immune cell-associated lncRNA (TIIClncRNA) in low-grade glioma (LGG), which has never been uncovered yet. Methods: This study utilized a novel computational framework and 10 machine learning algorithms (101 combinations) to screen out TIIClncRNAs by integratively analyzing the sequencing data of purified immune cells, LGG cell lines, and bulk LGG tissues. Results: The established TIIClnc signature based on the 16 most potent TIIClncRNAs could predict outcomes in public datasets and the Xiangya in-house dataset with decent efficiency and showed better performance when compared with 95 published signatures. The TIIClnc signature was strongly correlated to immune characteristics, including microsatellite instability, tumor mutation burden, and interferon γ, and exhibited a more active immunologic process. Furthermore, the TIIClnc signature predicted superior immunotherapy response in multiple datasets across cancer types. Notably, the positive correlation between the TIIClnc signature and CD8, PD-1, and PD-L1 was verified in the Xiangya in-house dataset. Conclusions: The TIIClnc signature enabled a more precise selection of the LGG population who were potential beneficiaries of immunotherapy.
Extracellular Vesicles and Circulating Tumour Cells - complementary liquid biopsies or standalone concepts?
Authors: Artur Słomka, Bingduo Wang, Tudor Mocan, Adelina Horhat, Arnulf G. Willms, Ingo G.H. Schmidt-Wolf, Christian P. Strassburg, Maria A. Gonzalez-Carmona, Veronika Lukacs-Kornek, Miroslaw T. Kornek
Journal: Theranostics (2022)

Liquid biopsies do promise a lot, but are they keeping it?In the past decade, additional novel biomarkers qualified to be called like that, of which, some took necessary hurdles resulting in FDA approval and clinical use.Some others are since a while around, well known and were once regarded to be a game changer in cancer diagnosis or cancer screening.But, during their clinical use limitations were observed from statistical significance and questions raised regarding their robustness, that eventually led to be dropped from associated clinical guidelines for certain applications including cancer diagnosis.The purpose of this review isn't to give a broad overview of all current liquid biopsy as biomarkers, weight them and promise a brighter future in cancer prevention, but rather to take a deeper look on two of those who do qualify to be called liquid biopsies now or then.These two are probably of greatest interest conceptually and methodically, and likely have the highest chances to be in clinical use soon, with a portfolio extension over their original conceptual usage.We aim to dig deeper beyond cancer diagnosis or cancer screening.Actually, we aim to review in depth extracellular vesicles (EVs) and compare with circulating tumour cells (CTCs).The latter methodology is partially FDA approved and in clinical use.We will lay out similarities as taking advantage of surface antigens on EVs and CTCs in case of characterization and quantification.But drawing readers' attention to downstream application based on capture/isolation methodology and simply on their overall nature, here apparently being living material eventually recoverable as CTCs are vs. dead material with transient effects on recipient cell as in case of EVs.All this we try to bring in perspective, compare and conclude towards which future direction we are aiming for, or should aim for.Do we announce a winner between CTCs vs EVs? No, but we provide good reasons to intensify research on them.
Antigen transfer and its effect on vaccine-induced immune amplification and tolerance
Authors: Yingying Shi, Yichao Lu, Jian You
Journal: Theranostics (2022)

Antigen transfer refers to the process of intercellular information exchange, where antigenic components including nucleic acids, antigen proteins/peptides and peptide-major histocompatibility complexes (p-MHCs) are transmitted from donor cells to recipient cells at the thymus, secondary lymphoid organs (SLOs), intestine, allergic sites, allografts, pathological lesions and vaccine injection sites via trogocytosis, gap junctions, tunnel nanotubes (TNTs), or extracellular vesicles (EVs).In the context of vaccine inoculation, antigen transfer is manipulated by the vaccine type and administration route, which consequently influences, even alters the immunological outcome, i.e., immune amplification and tolerance.Mainly focused on dendritic cells (DCs)-based antigen receptors, this review systematically introduces the biological process, molecular basis and clinical manifestation of antigen transfer.
CRISPR/Cas9-based genome-wide screening for deubiquitinase subfamily identifies USP1 regulating MAST1-driven cisplatin-resistance in cancer cells
Authors: Apoorvi Tyagi, Kamini Kaushal, Arun Pandian Chandrasekaran, Neha Sarodaya, Soumyadip Das, Chang-Hwan Park, Seok-Ho Hong, Kye-Seong Kim, Suresh Ramakrishna
Journal: Theranostics (2022)

Background: Cisplatin is one of the frontline anticancer agents.However, development of cisplatin-resistance limits the therapeutic efficacy of cisplatin-based treatment.The expression of microtubule-associated serine/ threonine kinase 1 (MAST1) is a primary factor driving cisplatin-resistance in cancers by rewiring the MEK pathway.However, the mechanisms responsible for MAST1 regulation in conferring drug resistance is unknown.Methods: We implemented a CRISPR/Cas9-based, genome-wide, dual screening system to identify deubiquitinating enzymes (DUBs) that govern cisplatin resistance and regulate MAST1 protein level.We analyzed K48-and K63-linked polyubiquitination of MAST1 protein and mapped the interacting domain between USP1 and MAST1 by immunoprecipitation assay.The deubiquitinating effect of USP1 on MAST1 protein was validated using rescue experiments, in vitro deubiquitination assay, immunoprecipitation assays, and half-life analysis.Furthermore, USP1-knockout A549 lung cancer cells were generated to validate the deubiquitinating activity of USP1 on MAST1 abundance.The USP1-MAST1 correlation was evaluated using bioinformatics tool and in different human clinical tissues.The potential role of USP1 in regulating MAST1mediated cisplatin resistance was confirmed using a series of in vitro and in vivo experiments.Finally, the clinical relevance of the USP1-MAST1 axis was validated by application of small-molecule inhibitors in a lung cancer xenograft model in NSG mice. Results:The CRISPR/Cas9-based dual screening system identified USP1 as a novel deubiquitinase that interacts, stabilizes, and extends the half-life of MAST1 by preventing its K48-linked polyubiquitination.The expression analysis across human clinical tissues revealed a positive correlation between USP1 and MAST1.USP1 promotes MAST1-mediated MEK1 activation as an underlying mechanism that contributes to cisplatin-resistance in cancers.Loss of USP1 led to attenuation of MAST1-mediated cisplatin-resistance both in vitro and in vivo.The combined pharmacological inhibition of USP1 and MAST1 using small-molecule inhibitors further abrogated MAST1 level and synergistically enhanced cisplatin efficacy in a mouse xenograft model.Conclusions: Overall, our study highlights the role of USP1 in the development of cisplatin resistance and uncovers the regulatory mechanism of MAST1-mediated cisplatin resistance in cancers.Co-treatment with USP1 and MAST1 inhibitors abrogated tumor growth and synergistically enhanced cisplatin efficacy, suggesting a novel alternative combinatorial therapeutic strategy that could further improve MAST1-based therapy in patients with cisplatin-resistant tumors.
A CRISPR-Cas12a integrated SERS nanoplatform with chimeric DNA/RNA hairpin guide for ultrasensitive nucleic acid detection
Authors: Bohan Yin, Qin Zhang, Xinyue Xia, Chuanqi Li, Willis Kwun Hei Ho, Jiaxiang Yan, Yingying Huang, Honglian Wu, Pui Wang, Changqing Yi, Jianhua Hao, Jianfang Wang, Honglin Chen, Siu Hong Dexter Wong, Mo Yang
Journal: Theranostics (2022)

CRISPR-Cas12a has been integrated with nanomaterial-based optical techniques, such as surface-enhanced Raman scattering (SERS), to formulate a powerful amplification-free nucleic acid detection system. However, nanomaterials impose steric hindrance to limit the accessibility of CRISPR-Cas12a to the narrow gaps (SERS hot spots) among nanoparticles (NPs) for producing a significant change in signals after nucleic acid detection.